Manufacture of meso-halogeno-aza-



Patented Aug. 25,1953

i D STATES PATENT oriucr.

MANUFACTURE OF MESO-HALOGENO-AZAL ncRmINEs Alan August Goldberg,

Donald Maurice Besl ors to Ward Blenkinsop & Company a British companyLondon, England,

Hamp'stead, London, and

y, Wells, England, assign- Limited,

No Drawing. ApplicationuMay 14,]1951, Serial No. 226,274. InGreatBritain May 17, 1950 16 Claims. (01; 2s0 2ss) The invention relatestothemanufacture of meso halogeno aza-acridines (pyridoquinolines)represented by the formula 696,127) of the general formula N 7 -oo H Tm-NH wherein R and R areas above defined can be treated with a phosphory1halide whereupon simultaneous cyclisation and halogenation takes placewith formation of the corresponding mesohalogeno aza-acridine.

Cyclisation occurs exclusively on to the position ortho to theheterocyclic nitrogen of the pyridine ring, 1. e. the compounds obtainedaccording to the invention are derivatives of Lazaa'cridine. Welldefined crystalline compounds have been obtained. 7 it According to theinvention the new compounds are also obtained by the cyclodehydration ofthe appropriately substituted 3'-aza-diphenylamine- Z-carboxylicacid bymethods which are known to effect the cyclodehydration of diphenylamine-Z-carboxylic acids to acridones and the isolation of the resultingsubstituted 1- or 3-aza-acridone thus produced; the latter are thenconverted into the meso-halogeno l-aza acridines by treatment with aphosphoryl halide. Known reagents for effecting cyclodehydration ofdiphenylamine-2- carboxylic acids are, sulphuric acid, mixtures ofsulphuric acid and phosphoric acid and boron trioxide, mixtures ofsulphuric acid and acetic anhydride, mixtures of acetic anhydride andacetyl chloride; a further known method for convertingdiphenylamine-2-carboxylic acids to acridones consists in preparing thediphenylamine-Z-carboxyl chloride and effecting cyclisation by addi- 2dines. For examples, Kermack and Weatherhead (J. Chem. $00., 1942, 726),Petrow (J. Chem. Soc., 1945, 927) and Bachman and Barker (J. Org.Chem.,1949, volume 14, 97) all state that it was found impossible tocyclise 3'-aza-diphenylamine- Z-carboxylic acid and4'-aza-diphenylamine-2 carboxylic acid. Moreover, Bachman and Barker(10cc cit.) state that although they effected cyclisation of 3:5dimethyl 4-aza-diphenylamine-2carboxylic acid to give 1:3-dimethyl-2-aza-acridone it was impossible to convert this into the desiredmeso-halogeno aza-acridine.

A preferred process for the manufacture of meso-halogeno-aza-acridinescomprises heating the appropriately substituted ortho-(pyrid-S-ylamino)benzoic acid, or the corresponding azaacridone derived therefrom bycyclisation, with phosphoryl chloride; the said ortho-pyridylaminobenzoic acid may have as a nuclear substituent in the ring carryingthe carboxyl group, a,

halogen atom (for example, chlorine or bromine) or an alkoxy or nitrogroup whilst the pyridyl alkoxy, or aryloxy group in theposition para tothe NH-. the ring; carrying the carboxyl group is preferably present;

ring has as a nuclear substituent an bridge. The nuclear substituent inin the 4- or 5-position.

ammonia and ice to release the aza-acridine base.

An alternative method of cyclisation of the-: ortho-pyridylaminobenzoicacid is to heat it with; phosphoric acid or with a mix-. aceticanhydride. This; l-aza-acridone and the; latter may then be convertedinto the corre-- sponding meso-halogeno aza-acridine by reflux-- ingwith a phosphoryl oxyhalide and the reaction;

sulphuric and/or ture of sulphuric acid and results in formation of amixture treated as described above.

Suitable starting materials for the production of the aza-acridines ofthe invention are the. 5 halogeno 4' alkoxy 3eaza-diphenylamine2-carboxylic acids, the 5-halogeno-4-aryloxy-3' aza-diphenylamine2-carboxylic acids, th 4- alkoxyland -5-nitro-3-aza-diphenylamine 2-carboxylic acids and the 4.4-dialkoxy-3-aza-diphenylamine Z-carboxylicacids. Preferably the alkoxy group is a lower alkoxy group such asmethoxy, ethoxy, a propoxy, a butoxy, a pentoxy or hexoxy group. Thearyloxy group is preferably a low molecular weight aryloxy group such asphenoxy, tolyloxy or xylyloxy and the preferred halogens are chlorineand bromine. '7 Compounds which can be' thus obtained in has a meltingpoint of l86l87 C.

clude, 2-methoxy-6 :9-dichloro-1 aza acridine, 2-ethoxy-6;9-dichloro-laza acridine, 2 propoxy-6 :9-dichloro-leaza-acridine, 2 n butoxy- 6Q-dichIoro-aza-acridine, 2-phenoxy-6 :9-dichloro-l-aza-acridine, 2ethoxy-6-nitro-9-chloro-laza-acridine, 2-methoxy-"I-nitro-9-chloro-1-azaacridine, and 2 :7 dimethoxy .-i 9 chlorg-l-azaacridine.

Some of the products thusobtained are valuable intermediates formanufacturing compounds with antibacterial, antiplasmpdialandantiprotozoal activity. They have pharmacological value.

The following examples, in which all parts of solids are by weight andall parts of liquids are by volume in units of the c. g. s. system,illustrate the manner in which the invention may be carried into efiect:

EXAMPLE 1 Z-n-butoaty-B 9-,dichZoTo-. 1=aza-acrr11dine-chloro-4-n-butoxy-3'eaza diphenylamine- 2-carboxy1ic acid (12.8 parts)is refluxed with phosphorus oxychloride (128 parts) for 4 hours.Approximately two-thirds of the phosphorus oxychloride is removed bydistillation in vacuo, and the residue then poured on crushed ice, andscratched until it becomes solid and friable. The solid is filtered off,suspended in water which has been made alkaline by addition of a fewdrops of ammonia and stirred for a short time.

The product, which is light yellow in colour, is filtered off and driedover sulphuric acid in vacuo. The yield is 12.8 parts (theoreticalyield) and the product has .a melting pointo-f 12l-124 Onecrystallization from acetone raises the melting point to 127f128 C.(Found (on twice crystallised material of this melting point): .N, 8.9%;Cl, 22.0%. .CrsHmONzClz requires: N,

' EXAMPLE 2 hoxy-fi 9-d2'chloro-1 -aza-acridine addition of a fewdropsof ammonia and stirred.

The lighteyellow product is filtered off and dried over sulphuric acidin vacuo. It has a melting point of 181-184"- C. (incomplete) andamounts to 5.3 parts which represents a yield of 98% theory.

The compound crystallises from acetone and (Found: N, 10.4%; C1, 24.9%.CisI-IsONzClz requires: N, 10.0%; C1, 25.4%.)

EXAMPLE 3 Z-phenomy-G :Q-dichloro-I -.a2a.-ac'ridine 25 parts of4-phenoxy-.5-chloro 3' aza-diphenyIamine-Z-carboxylic acid are refluxedwith 150 partsof -phosphorus, oxychlorideior 5 hours. About one-halfor-two-thirds of the phosphorus oxychloride is distilled off underreduced pres.- sure and'the residue slowly poured into a stirred mixtureof 30003133113 of crushed ice. and 1000 par-ts of ammonia- (D, 0.880).The product is collected, washed; and dried; over sulphuricacidmi-vacumsth yield is,25 .;parts.M. P. ,174- .Re-

4 crystallisation from a large volume of ligroin (B. P. /100) gives thepure compound as an almost colourless microcrystalline powder M. P. 184C. It is very soluble in hot chloroform. (Found: N, 8.2; Cl, 20.5CmHmONzClz requires: N, 8.2; C1, 20.8%.)

EXAMPLE 4 2-methoa:y-7-nitro-9-chZoro-1 mew-maritime 1 parts of 4methoxy-4 nitro 3 aza diphenylamine-Zcarboxy1ic acid are refluxed forEXAMPLE 5 2-ethoxy-6-nit1'o-9-chZoro-1-a2a-acridine By substituting.4-ethoxy-5-nitro-3 aza diphenylamine-Z-carboxylic acid for the4'-methoxy-4-nitro 3 aza diphenylamine 2 carboxylic acid in Example 3there is obtained in like manner 2-ethoxy-6-nitro-9-chloro 1 azaacridinein high yield.

EXAMPLE 6 2 7 -dimethoa:y-9-choloro-1 -azaacr1idine 50 parts of4:4-dimethoxy-3aza-diphenylamine-Z-carboxylic acid are refluxed for 4hours with 300 parts of phosphorus oxychloride. About one-half of thephosphorus oxychloride i distilled off at reduced pressure .and theresidue poured with stirring into a mixture of 800 parts of ammonia (D.0.880) and 3000 parts of crushed ice. The precipitate is collected,washed and dried in vacuo over sulphuric acid. The yield is 50 parts M.P. 212-214 C. The pure compound, obtained by recrystallisation from alarge Volume of ligroin (B. P. 80/100) has M. P. 218- 220". (Found: N,10.4; CI, 13.2. C 14H11O2N2C1 requires: N, 10.2; C1, 12.9%.)

EXAMPLE '7 2 :7 -dimethomy-9-choZoro-1 -aaa-acridine A solution of 50parts of 4:4dimethoxy-3'- aza-diphenylamine-Z-carboxylic acid in 500parts of sulphuric acid is heated on the water-bath for 1 hour andpoured on to ice. The precipitate of 2 :'7-dimeth-oxy-1-azaacridone;iscollected, and crystallised .from alcoholic pyridine; the product isobtained in yellow crystals M. Prabove 300 C. (Found: N, 10.9.C14H12O3N2 requires: N, 10.9%.) 50 parts of 2:7-dimethoxy-1-aza-acridoneare refluxed for 4 hours with 400 parts of phosphorus oxychloride. Byisolating the product in the same manner as described'in Example 6 thereis obtained a good yield of 2:7-dimethoxy-Q-ch1oro-1-aza-acridine.

Whatwe claim is:

1. A meso halogeno-l-aza-acridine havingthe in, which R is: selectedfrom the group consisting; ofghydro en; .l-Ialogen, loweralkoxy and,nitro Hal and R is selected from the group consisting of lower alkoxyand aryloxy groups and Hal is a halogen atom.

2. A meso halogeno l-aza-acridine having the general formula Hal R1 \Nin which R is selected from the group consisting of hydrogen halogen,lower alkoxy and nitro and R is selected from the group consisting oflower alkoxy and aryloxy groups and Hal is a halogen atom.

3. A meso halogeno l-aza-acridine having the general formula Hal inwhich R is selected from the group consisting of hydrogen, halogen,lower alkoxy and nitro and R. is selected from the group consisting oflower alkoxy and aryloxy groups and Hal is a halogen atom whichcomprises treating an orthopyrid-(3-yl)-aminobenzoic acid having thegeneral formula N COOH R R1 in which R and R are as above defined with aphosphoryl halide and isolating the product.

10. A method of producing a meso-halogenol-aza-acridine having thegeneral formula Hal OOOH R R1 NE in which R and R. are as above definedwith a phosphoryl halide and isolating the product.

11. The method according to claim 10 in which saidortho-pyrid-(3-y1)-aminobenzoic acid is 5- chloro 4 1 methoxy 3 1 azadiphenylamine- Z-carboxylic acid.

12. The method according to claim 10 in which saidortho-pyrid-(B-yl)-aminobenzoic acid is 5- chloro 4 1 n butoxy 3 1 azadiphenylamine-2-carboxylic acid.

13. The method according to claim 10 in which saidortho-pyrid-(B-yl)-aminobenzoic acid is 5- chloro 4 1 phenoxy 3 1 azadiphenylamine- 2-carboxylic acid.

14. The method according to claim 10 in which saidortho-pyrid-(3-yl)-aminobenzoic acid is 5- nitro 4 1 ethoxy 3 1 azadiphenylamine-ilcarboxylic acid.

15. A method of producing a meso-halogeno-laza-acridine having thegeneral formula Hal in which R is selected from the group consisting ofhydrogen, halogen, R is selected from the group consisting of loweralkoxy and aryloxy groups and Hal is a halogen atom which comprisestreating an ortho-pyrid- (3-yl) -aminobenzoic acid having the generalformula in which R and 1i. are as above defined with a phosphoryl halideand isolating the product.

16. The method according to claim 15 in which saidortho-pyrid-(E-yl)-aminobenzoic acid is 4- nitro 4 1 methoxy 3 1 azadiphenylamine- 2-carboxylic acid.

ALAN AUGUST GOLDBERG. DONALD MAURICE BESLY.

References Cited in the file of this patent Bachman et a1.: J. Org.Chem, vol. 14, pp. 97- 104 (1949).

Fieser et a1.: Organic Chemistry (D. C. Health and Co.; Boston 1944),page 32.

lower alkoxy and nitro and

1. A MESO-HALOGENO-1-AZA-ACRIDINE HAVING THE GENERAL FORMULA